The significance and nature of this collaboration fits very well with the thematic areas applying genomics and other high throughput technologies, translating basic science discoveries into new and better treatment, using science to enable health care reform, and reinvigorating the biomedical community. Diabetes predominantly affects the microvascular circulation of the retina and results in a range of microvascular structural changes that are unique to this tissue. The clinical course of diabetic retinopathy is classified into stages reflecting the progression of the disease and the prognostic risk of blindness. It is assumed that the full spectrum of diabetic retinal microangiopathy arises from a continuum, and that one stage of the disease is likely to lead to another, more advanced stage with a greater risk for blindness. These stages include "no retinopathy", "nonproliferative", and (mild, moderate, severe) "proliferative" retinopathy. Two of the earliest histopathological lesions, diffuse thickening of the basement membrane and selective loss of pericytes, go undetected by routine fundus examinations. Our hypothesis is that these changes have significant impact on retinal vascular hemodynamic and oxygenation, which can be detected non-invasively, utilizing a novel multimodal imaging methodology developed by our group. Here we have assembled a team of investigators to take full advantage of the frontiers of computational, engineering, biological, and biochemical analysis to address a major clinical concern, namely detection of early retinopathies associated with diabetes. As a proof of concept, we purpose to further develop and adopt a multimodal retinal functional imaging, complemented with various high throughput biochemical and computational analysis for study of early diabetic changes in novel mouse models of diabetes developed by our group. We will utilize metabolomic changes of the retina and serum prepared from animals with different duration of diabetes, as well as gene expression profiling of retinal samples, and retinal vascular cells under normal and high glucose, to further identify specific early changes during diabetes. Our group has developed and has the expertise to design and implement unique algorithm for large data set analysis and modeling based on specific genotypic and phenotypic variations. In addition, we have computational expertise to improve our imaging capabilities and qualities. Our team will be able to successfully implement the research proposed here and integrate our findings in a meaningful way which could be readily adapted for diagnosis and treatment strategies in humans. Detection and identification of the molecular and cellular bases of early changes that progress to advance stages of the disease will allow for a better diagnosis, prevention and treatment modalities. PUBLIC HEALTH RELEVANCE: Diabetes affects retinal circulation resulting in vascular abnormalities that ultimately lead to aggressive growth of new vessels and loss of vision. A clear understanding of how these changes are brought about, and their early non-invasive detection and identification of their molecular and cellular bases, are essential in advancing our understanding of diabetic retinopathy. This knowledge will lead to the development of better and more effective therapies. Factors that keep retinal vasculature in check, such as thrombospondin-1 and vascular endothelial growth factor play a major role in normal retinal vascular function. Alterations in these factors during diabetes may contribute to abnormal vascular function and growth of new blood vessels. Increased production of vascular endothelial growth factor, which promotes growth of new vessels and alters vascular permeability, has been demonstrated during diabetes. Here Dr. Sheibani and his team of collaborators will utilize an integrated strategy to detect and determine the biochemical and gene specific changes, such as thrombospondin-1, in development and progression of retinopathies during diabetes. This knowledge will be instrumental in accelerating our progress in the understanding, detection, and treatment of diabetic retinopathy.